Morphine or other bimodally-acting opioid agonists are administered to relieve severe pain due to the fact that they have analgesic effects mediated by their activation of inhibitory opioid receptors on nociceptive neurons (see North, Trends Neurosci., Vol. 9, pp. 114-117 (1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81 (1990)). However, morphine and other bimodally-acting opioid agonists also activate opioid excitatory receptors on nociceptive neurons, which attenuate the analgesic potency of the opioids and result in the development of physical dependence and increased tolerance (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83 (1992)), as well as hyperexcitability, hyperalgesia and other undesirable (excitatory) side effects. As a result, a long-standing need has existed to develop a method of both enhancing the analgesic (inhibitory) effects of bimodally-acting opioid agonists and blocking or preventing undesirable (excitatory) side effects caused by such opioid agonists.
Tramadol is an orally active, clinically effective, centrally acting analgene compound with opioid and non-opioid activity. This synthetic analgesic has a novel mechanism of action involving a complementary and synergistic interaction between inhibition of neuronal monamine uptake and weak affinity for opioid receptors (Raffa et al., Rev. Contemp. Pharmacother. 6:485-497 (1995)). Tramadol is generally well tolerated, with dizziness, nausea, constipation, headache, somnolence (sedation), vomiting, pruritis, CNS stimulation, sezures, asthenia, dyspepsia, diarrhea, dry mouth and/or sweating as adverse side effects. Respiratory depression is uncommon (Lee et al., Drugs 46: 313-340 (1993); Vickers et al., Anaesthesia 47: 291-296 (1992)). Tramadol is marketed in the United States as ULTRAM(copyright). Data from a double-blind, crossover study suggest that oral tramadol 120 mg is equipotent to oral morphine 30 mg (Wilder et al., Ann. Oncol. 5: 141-146 (1994)). A need thus exists for compositions and methods that could enhance the analgesic potency of tramadol and/or block or prevent its adverse side effects, particularly its principal adverse effects in humans.
The present invention is directed to compositions and methods for enhancing analgesic potency of tramedol and/or attenuating (e.g. reducing, blocking, inhibiting or preventing) its adverse effects, particularly its adverse side effects in humans. Principle adverse side effects of tramadol in humans include dizziness, nausea, constipation, headache, somnolence (sedation), vomiting, pruritis, CNS stimulation, seizures, asthenia, dyspepsia, diarrhea, dry mouth and/or sweating.
The present invention is directed to a method for selectively enhancing the analgesic potency and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the tramadol. The method comprises administering to a subject an analgesic or sub-analgesic amount of tramadol and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the tramadol and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the tramadol.
The present invention also provides a method for treating pain in a subject comprising administering to the subject an analgesic or sub-analgesic amount of tramadol and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the tramadol and attenuate anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the tramadol.
The present invention provides a composition comprising an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist in a subject administered the composition.
The present invention provides a method for enhancing the potency of tramadol in a human subject by administering to the human subject an analgesic or subanalgesic amount of tramadol and an amount of an opioid antagonist effective to enhance the analgesic potency of the tramadol. Preferred opioid antagonists include naltrexone, naloxone, or nalmefene.
The present invention also provides a method for attenuating an adverse side effect associated with the administration of tramadol to a human subject by administering to the human subject an analgesic or subanalgesic amount of tramadol and an amount of an opioid antagonist effective to attenuate the adverse side effect. Adverse side effects include, but are not limited to, nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritis. Analgesic potency of the agonist may be maintained while one or more side effects are attenuated, without increasing or decreasing the cumulative daily dose of agonist.
The present invention further provides a method for treating pain in a human subject by administering to the human subject an analgesic or subanalgesic amount of tramadol and an amount of an opioid antagonist effective to enhance the analgesic potency of tramadol, as well as a method for treating pain with tramadol and attenuating an adverse side effect of tramadol in a human subject by administering to the human subject an analgesic or subanalgesic amount of tramadol and an amount of an opioid antagonist effective to attenuate the adverse side effect.
The present invention provides a composition of an analgesic or subanalgesic amount of tramadol and an amount of an opioid antagonist effective to enhance the analgesic potency of tramadol. The present invention also provides a composition of an analgesic or subanalgesic amount of tramadol and an amount of an opioid antagonist effective to attenuate an adverse side effect of tramadol.
Compositions and methods of the present invention thus solve the problem of a less than desired analgesic potency and/or adverse side effects associated with tramadol administration in humans.